The genetics of systemic lupus erythematosus: putting the pieces together

Kelly, Jennifer A.; Moser, Kathy L.; Harley, John B.

doi:10.1038/sj.gene.6363885

Cited by 134 publications

(96 citation statements)

References 126 publications

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“…The etiology of SLE has a definite genetic component as inferred from increased familial aggregation among siblings and an increased concordance rate among monozygotic twins compared to dizygotic twins. [1][2][3] This is further supported by the identification of genetic associations of candidate gene polymorphisms 4,5 as well as the establishment of linkage to loci in genome-wide scans in SLE. [6][7][8][9][10][11][12] In man, SLE is not often a single gene disorder; the genetic effect generally appears to be conferred by polymorphisms in multiple genes.…”

Section: Introductionmentioning

confidence: 92%

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

et al. 2005

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Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC C/T as well as the FASÀ670G4A 0 -codon214 AC C/T 0 haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FASÀ670G, which affects STAT1 binding, leads to the highest activity. FASLÀ844C activity is modified by the cis acting À478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

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Section: Introductionmentioning

confidence: 92%

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

et al. 2005

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“…4,5 A number of susceptibility genes, such as HLA, mannose-binding lectin gene, C4A, FcgR, tumor-necrosis factor-a (TNF-a), programmed cell death 1 gene (PDCD1) and interleukin-10 (IL-10), have been associated with SLE among various populations. [6][7][8][9][10][11] IL-10 is a pleiotropic cytokine produced by both T/B cells and macrophages and possesses both anti-inflammatory and immunosuppressive properties. 12 Investigations in numerous inflammatory disease models including chronic enterocholitis, cutaneous inflammatory condition, endotoxic shock and Shwartzman reaction, and autoimmune encephalomyelitis in IL-10-deficient mice have yielded strong evidence that IL-10 plays a central role in vivo in restricting inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

et al. 2007

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Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease characterized by the dysregulation of T and B cells that leads to hyperactivity of B cells and production of autoantibodies, and involves both environmental and genetic factors. Interleukin-10 (IL-10) is a candidate susceptibility gene in SLE. In particular, three IL-10 promoter singlenucleotide polymorphisms (SNPs; À1082A/G, À819T/C and À592A/C) are strongly associated with the pathogenesis of SLE. We found that the homozygous GCC haplotype linked to greater SLE severity confers higher IL-10 gene transcriptional activity than the ATA haplotype in macrophages that encounter apoptotic cells, because of the differential DNA binding to the À592 SNP by a nuclear protein uniquely induced by apoptotic cells. We identified this protein as poly(ADP-ribose) polymerase-1, confirmed its physiological role and characterized its molecular properties in modulating IL-10 production during phagocytosis of apoptotic cells. This study unveils a novel direct link between DNA damage repair/apoptosis pathways and IL-10-mediated immune regulation.

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“…Twin studies have suggested that heritability accounts for 30-40% of the overall susceptibility to SLE (7); other "nongenetic" or environmental factors may also be involved in SLE etiology. A variety of susceptibility genes have been identified (8)(9)(10)(11)(12)(13); however, none of the genes identified to date adequately explain the elevated risk of SLE observed in people of sub-Saharan African ancestry.…”

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confidence: 99%

Effect of glutathione S‐TRANSFERASE polymorphisms and proximity to hazardous waste sites on time to systemic lupus erythematosus diagnosis: Results from the roxbury lupus project

Karlson¹,

Watts²,

Signorovitch³

et al. 2007

Arthritis & Rheumatism

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Objective. The high prevalence of systemic lupus erythematosus (SLE) among African American women may be due to environmental exposures, genetic factors, or a combination of factors. Our goal was to assess association of residential proximity to hazardous waste sites and genetic variation in 3 glutathione Stransferase (GST) genes (GSTM1, GSTT1, and GSTP1) with age at diagnosis of SLE.Methods. Residential histories were obtained by interviewing 93 SLE patients from 3 predominantly African American neighborhoods in Boston. Residential addresses and locations of 416 hazardous waste sites in the study area were geocoded using ArcView software. Time-varying Cox models were used to study the effect of residential proximity to hazardous sites, GST genotype, and interaction between genotype and exposure in determining age at diagnosis.Results. The prevalence of SLE among African American women in these neighborhoods was 3.56 SLE cases per 1,000. Homozygosity for GSTM1-null and GSTP1 Ile105Val in combination was associated with earlier SLE diagnosis (P ‫؍‬ 0.03), but there was no association with proximity to 416 hazardous sites. Available data on specific site contaminants suggested that, at a subset of 67 sites, there was higher potential risk for exposure to volatile organic compounds (P < 0.05 with Bonferroni correction). GST genotypes had a significant interaction with proximity (P ‫؍‬ 0.03) in analyses limited to these sites.Conclusion. There was no independent association between residential proximity to hazardous waste sites and the risk of earlier SLE diagnosis in this urban population. However, analysis of a limited number of sites indicated that the risk of earlier SLE associated with proximity to hazardous sites might be modulated by GST polymorphisms.

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The genetics of systemic lupus erythematosus: putting the pieces together

Cited by 134 publications

References 126 publications

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

Effect of glutathione S‐TRANSFERASE polymorphisms and proximity to hazardous waste sites on time to systemic lupus erythematosus diagnosis: Results from the roxbury lupus project

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